This invention relates to the fields of pharmaceutical and organic chemistry and provides novel 1-benzyl napthyls which are xcex1-substituted with ether, thioether, amine, hydrazine, cyano, or halo, which are useful for the treatment of the various medical indications associated with post-menopausal syndrome, as well as estrogen dependent diseases including cancer of the breast, uterus and cervix. The present invention further relates to intermediate compounds and processes useful for preparing the pharmaceutically active compounds of the present invention, and pharmaceutical compositions.
xe2x80x9cPost-menopausal syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, three major effects of post-menopausal syndrome are the source of the greatest long-term medical concern: osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer, particularly breast and uterine cancer.
Osteoporosis describes a group of diseases which arise from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of mensus. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of post-menopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which inter-connect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This inter-connected network of trabeculae gives lateral support to the outer cortical structure and is critical to the bio-mechanical strength of the overall structure. In post-menopausal osteoporosis, it is, primarily, the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in post-menopausal women, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae, the neck of,the weight bearing bones such as the femur and the fore-arm. Indeed, hip fracture, collies fractures, and vertebral crush fractures are hall-marks of post-menopausal osteoporosis.
At this time, the only generally accepted method for treatment of post-menopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low primarily because estrogen treatment frequently produces undesirable side effects.
Throughout premenopausal time, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that post-menopausal women having estrogen replacement therapy have a return of serum lipid levels to concentrations to those of the pre-menopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side-effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which would regulate the serum lipid level as does estrogen, but would be devoid of the side-effects and risks associated with estrogen therapy.
The third major pathology associated with post-menopausal syndrome is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasms are not solely limited to a post-menopausal women, they are more prevalent in the older, post-menopausal population. Current chemotherapy of these cancers has relied heavily on the use of anti-estrogen compounds such as, for example, tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be contraproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an anti-estrogen compound having negligible or no estrogen agonist properties on reproductive tissues.
In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of, inter alia, post-menopausal syndrome, the present invention provides new compounds, pharmaceutical compositions thereof, and methods of using such compounds for the treatment of post-menopausal syndrome and other estrogen-related pathological conditions such as those mentioned below.
Uterine fibrosis (uterine fibroid disease) is an old and ever present clinical problem which goes under a variety of names, including uterine fibroid disease, uterine hypertrophy, uterine lieomyomata, myometrial hypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterine fibrosis is a condition where there is an inappropriate deposition of fibroid tissue on the wall of the uterus.
This condition is a cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood but evidence suggests that it is an inappropriate response of fibroid tissue to estrogen. Such a condition has been produced in rabbits by daily administrations of estrogen for 3 months. In guinea pigs, the condition has been produced by daily administration of estrogen for four months. Further, in rats, estrogen causes similar hypertrophy.
The most common treatment of uterine fibrosis involves surgical procedures both costly and sometimes a source of complications such as the formation of abdominal adhesions and infections. In some patients, initial surgery is only a temporary treatment and the fibroids regrow. In those cases a hysterectomy is performed which effectively ends the fibroids but also the reproductive life of the patient. Also, gonadotropin releasing hormone antagonists may be administered, yet their use is tempered by the fact they can lead to osteoporosis. Thus, there exists a need for new methods for treating uterine fibrosis, and the methods of the present invention satisfy that need.
Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition appear to be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissue seems to initiate local inflammatory-like responses causing macrophage infiltration and a cascade of events leading to initiation of the painful response. The exact etiology of this disease is not well understood and its treatment by hormonal therapy is diverse, poorly defined, and marked by numerous unwanted and perhaps dangerous side effects.
One of the treatments for this disease is the use of low dose estrogen to suppress endometrial growth through a negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen; however, it is sometimes necessary to use continuous estrogen to control the symptoms. This use of estrogen can often lead to undesirable side effects and even the risk of endometrial cancer.
Another treatment consists of continuous administration of progestins which induces amenorrhea and by suppressing ovarian estrogen production can cause regressions of the endometrial growths. The use of chronic progestin therapy is often accompanied by the unpleasant CNS side effects of progestins and often leads to infertility due to suppression of ovarian function.
A third treatment consists of the administration of weak androgens, which are effective in controlling the endometriosis; however, they induce severe masculinizing effects. Several of these treatments for endometriosis have also been implicated in causing a mild degree of bone loss with continued therapy. Therefore, new methods of treating endometriosis are desirable.
Smooth aortal muscle cell proliferation plays an important role in diseases such as atherosclerosis and restenosis. Vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been shown to be a tissue response characterized by an early and late phase. The early phase occurring hours to days after PTCA is due to thrombosis with some vasospasms while the late phase appears to be dominated by excessive proliferation and migration of aortal smooth muscle cells. In this disease, the increased cell motility and colonization by such muscle cells and macrophages contribute significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular aortal smooth muscle cells may be the primary mechanism to the reocclusion of coronary arteries following PTCA, atherectomy, laser angioplasty and arterial bypass graft surgery. See xe2x80x9cIntimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplasty,xe2x80x9d Austin et al., Journal of the American College of Cardiology, 8: 369-375 (August 1985).
Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by percutaneous transluminal coronary angioplasty (PTCA), atherectomy, laser angioplasty and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonist, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for the treatment and prevention of vascular restenosis. See xe2x80x9cPrevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a xe2x80x98Magic Bulletxe2x80x99,xe2x80x9d Hermans et al., American Heart Journal, 122: 171-187 (July 1991).
In the pathogenesis of restenosis excessive cell proliferation and migration occurs as a result of growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall which mediate the proliferation of smooth muscle cells in vascular restenosis.
Agents that inhibit the proliferation and/or migration of smooth aortal muscle cells are useful in the treatment and prevention of restenosis. The present invention provides for the use of compounds as smooth aortal muscle cell proliferation inhibitors and, thus inhibitors of restenosis.
The present invention relates to compounds of formula 
wherein R1 is H, OH, OCO(C1-C6 alkyl), OCO(aryl), OSO2(C4-C6 alkyl), OCOO(C1-C6 alkyl), OCOO(aryl), OCONH(C1-C6 alkyl), or OCON(C1-C6 alkyl)2;
R2 is aryl, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-cyclohexanol;
R3 is O(CH2)2 or O(CH2)3;
R4 and R5 are optionally CO(CH2)3, CO(CH2)4, C1-C6 alkyl, or R4 and R5 combine to form, with the nitrogen to which they are attached, piperidine, morpholine, pyrrolidine, 3-methylpyrrolidine, 3,3-dimethylpyrrolidine, 3,4-dimethylpyrrolidine, azepine, or pipecoline;
R6 is O(C1-C6 alkyl), O(aryl), O(C1-C6 alkyl)aryl)), OCH2CH2cyano, O((C1-C6 alkyl)C1-C6 alcohol) OSO2CH3, OSO2C6H4CH3, SH, S(C1-C6 alkyl), cyano halo, 
xe2x80x83wherein each of R7 and R8 is taken separately and represents H, C1-C6-alkyl, 2-hydroxyethyl, or 2-fluoroethyl, or both R7 and R8 are taken together with the nitrogen and form a ring which is pyrrolidine, piperidine, azepine, or morpholine and which may optionally be substituted by one or two methyl groups, or 
xe2x80x83wherein each of R10 and R11 is taken separately and represents H or C1-C2, or both R10 and R11 are taken together with the nitrogen and represent a ring which is a pyrrolidine, piperidine, azepine or morpholine and which may optionally be substituted by one or two methyl groups, and R12 is hydrogen, methyl, or ethyl; and
pharmaceutically acceptable salts thereof.
The present invention further relates to pharmaceutical compositions containing compounds of formula I, optionally containing estrogen or progestin, and the use of such compounds, alone, or in combination with estrogen or progestin, for alleviating the symptoms of post-menopausal syndrome, particularly osteoporosis, cardiovascular related pathological conditions, and estrogen-dependent cancer. As used herein, the term xe2x80x9cestrogenxe2x80x9d includes steroidal compounds having estrogenic activity such as, for example, 17xcex2-estradiol, estrone, conjugated estrogen (Premarin(copyright)), equine estrogen, 17xcex2-ethynyl estradiol, and the like. As used herein, the term xe2x80x9cprogestinxe2x80x9d includes compounds having progestational activity such as, for example, progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like.
The compounds of the present invention also are useful for inhibiting uterine fibroid disease and endometriosis in women and aortal smooth muscle cell proliferation, particularly restenosis, in humans.
One aspect of the present invention includes compounds of formula I 
wherein R1 is H, OH, OCO(C1-C6 alkyl), OCO(aryl), OSO2(C4-C6 alkyl), OCOOC(C1-C6 alkyl) or OCOO(aryl), OCONH(C1-C6 alkyl), or OCON(C1-C6 alkyl)2;
R2 is aryl, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-cyclohexanol;
R3 is O(CH2)2 or O(CH2)3;
R4 and R5 are optionally CO(CH2)3, CO(CH2)4, C1-C6 alkyl, or R4 and R5 combine to form, with the nitrogen to which they are attached, piperidine, morpholine, pyrrolidine, 3-methylpyrrolidine, 3,3-dimethylpyrrolidine, 3,4-dimethylpyrrolidine, azepine, or pipecoline;
R6 is O(C1-C6 alkyl), O(aryl), O(C1-C6 alkyl)aryl)), OCH2CH2cyano, O((C1-C6 alkyl)C1-C6 alcohol) OSO2CH3, OSO2C6H4CH3, SH, S(C1-C6 alkyl), cyano halo, 
wherein each of R7 and R8 is taken separately and represents H, C1-C6-alkyl, 2-hydroxyethyl, or 2-fluoroethyl, or both R7 and R8 are taken together with the nitrogen and form a ring which is pyrrolidine, piperidine, azepine, or morpholine and which may optionally be substituted by one or two methyl groups, or 
xe2x80x83wherein each of R10 and R11 is taken separately and represents H or C1-C2, or both R10 and R11 are taken together with the nitrogen and represent a ring which is a pyrrolidine, piperidine, azepine or morpholine and which may optionally be substituted by one or two methyl groups, and R12 is hydrogen, methyl, or ethyl; and
pharmaceutically acceptable salts thereof.
General terms used in the description of compounds herein described bear their usual meanings. For example, xe2x80x9calkylxe2x80x9d refers to straight or branched aliphatic chains of 1 to 6 carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like. The term xe2x80x9carylxe2x80x9d, refers to phenyl and phenyl substituted once or twice with alkyl, C1-C6 alkoxy, hydroxy, nitro, or halo. xe2x80x9cHaloxe2x80x9d includes bromo, chloro, iodo and fluoro. The term xe2x80x9c(C1-C6 alkyl)arylxe2x80x9d refers to an alkyl chain substituted with aryl. The term xe2x80x9c(C1-C6 alkyl)C1-C6 alcoholxe2x80x9d refers to an alkyl chain substituted with a C1-C6 alcohol, such as methanol, ethanol, 1-propanol, and 1-butanol.
The compounds of the present invention can be made according to established procedures, such as those detailed in U.S. Pat. No. 4,230,862 which is incorporated by reference herein. Examples of the preparation of analogous compounds are provided in the U.S. Patents discussed above.
In the processes for preparing the compounds of the present invention, the starting material is a compound of formula II 
wherein
R is a hydroxy protecting group capable of resisting reduction by a reducing agent; and
R3, R4 and R5 are as defined above;
or a salt thereof.
Compounds of formula II are known in the art. Generally, a precursor of formula III 
is prepared via known procedures. Typically, the two hydroxy groups are protected by known hydroxy protecting groups which are capable of resisting acylation under standard Friedel-Crafts conditions (forming the R protecting groups of formula II compounds) and subsequent reduction by a strong reducing agent. Preferred hydroxy protecting groups are C1-C4 alkyl, and methyl is especially preferred. See, e.g., the above-incorporated United States patents, J. W. Barton, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. Mcomie (ed.), Plenum Press, New York, N.Y.; 1973, Chapter 2, and T. W. Green, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, Chapter 7.
Following preparation of the desired protected formula III precursor, the precursor is acylated, using standard Friedel-Crafts conditions, with a compound of formula IV 
wherein
R3, R4 and R5 are as defined above; and
R* is chloro, bromo, iodo, or an activating ester group. Preparation of formula IV compounds, as well as preferred acylation methods, are disclosed in the above-incorporated United States patents. When R4 and R5 each are not combined C1-C4 alkyl, methyl and ethyl are preferred. When R4 and R5 are combined, 1-piperidinyl and 1-pyrrolidinyl are preferred. Of these, the piperidino moiety is especially preferred.
Following acylation and, thus, preparation of a compound of formula II, compounds with an xcex1-carbinol are prepared by adding a formula II compound or a salt thereof, to an appropriate solvent, and then reacting the formula II compound with a reducing agent such as, for example, lithium aluminum hydride (LAH), under an inert gas such as nitrogen.
The amount of reducing agent used in this reaction is an amount sufficient to reduce the carbonyl group of formula II to form a carbinol of formula IIa: 
wherein R3, R4 and R are as defined above, or a salt thereof. Generally, a liberal excess of the reducing agent per equivalent of the substrate is used.
Appropriate solvents include any solvent or mixture of solvents which will remain inert under reducing conditions. Suitable solvents include diethyl ether, dioxane, and tetrahydrofuran (THF). The anydrous form of these solvents is preferred, and anhydrous THF is especially preferred.
The temperature employed in this step is that which is sufficient to effect completion of the reduction reaction. Ambient temperature, in the range from about 17xc2x0 C. to about 25xc2x0 C., generally is adequate.
The length of time for this step is that amount necessary for the reaction to occur. Typically, this reaction takes from about 1 to about 20 hours. The optimal time can be determined by monitoring the progress of the reaction via conventional chromatographic techniques.
The xcex1-carbinol products from this reaction may be extracted essentially via the method described in preparation 1, infra. The following schemes illustrate the preparation of compounds of formula I. 
The scheme as set out in Scheme 1 may be used for preparation of the xcex1-ether and xcex1-thioether compounds. In the case of the ether substitutions, the xcex1-carbinol is subjected to an acid, such as trifluoroacetic acid, in an appropriate solvent, such as methylene chloride, at approximately room temperature. Thereafter an alcohol ether precursor (R6aH) is added, and the hydroxy-protecting groups are removed via known methodology. In the alcohol ether precursor, R6a is O(C1-C6 alkyl), O(aryl), O(C1-C6 alkyl)aryl), OCH2CH2 cyano, or O((C1-C6 alkyl)C1-C6 alcohol).
For the thioether substitution, again the xcex1-carbinol compound is subjected to an acid, such as trifluoroacetic acid, in an organic solvent at room temperature. Thereafter, a thiol thioether precursor (R6bH) is added, and the hydroxy-protecting groups are removed via known methodology. In the thiol thioether precursor, R6a is OSO2CH3, OSO2C6H4CH3, SH, or S(C1-C6 alkyl). 
Scheme 2 above can be used for the preparation of the amino, hydrazino, cyano and halo xcex1-substitutions. In the case of the amino and hydrazino substitution, the xcex1-carbinol is subjected to a dehydrating agent or agents, such as methanesulfonyl chloride and triethylamine, in a solvent, such as methylene chloride, at approximately 0xc2x0 C. Thereafter, an amino or hydrazino precursor 
is added at room temperature. In the case of the cyano, again a dehydrating agent or agents are used as above and a cyano precursor such as potassium cyanide is added as well as a ligand such as a crown ether, particularly 18-crown-6, to aid in solubility. For the halo-xcex1 substitution again a dehydrating agent or agents is used and thereafter a halo precursor, such as a halo-containing salt, such as LiF, is added, as well as a solvent such as a crown ether, particularly 12-crown-4, to aid in solubility.
Other compounds are prepared by replacing the 4xe2x80x2- and 6-hydroxy groups with a different moiety, such as xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, or xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alky) via well known procedures. See, e.g., U.S. Pat. No. 4,358,593, supra.
For example, when a xe2x80x94Oxe2x80x94CO(C1-C6 alkyl) or xe2x80x94Oxe2x80x94COxe2x80x94Ar group is desired, the dihydroxy compound of formula I is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed with anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine, and the like. The reaction also may be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and the like, to which at least one equivalent of an acid scavenger, such as a tertiary amine, has been added. If desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e g., Haslam, et al., Tetrahedron, 36:2409-2433 (1980).
The acylation reactions which provide the aforementioned R1 and R2 groups are carried out at moderate temperatures in the range from about xe2x88x9225xc2x0 C. to about 100xc2x0 C., frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for the reaction to run.
Such acylations of the hydroxy group also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents or heat. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like are used.
The R1 and R2 groups also may be provided by forming an active ester of the appropriate acid, such as the esters formed by such known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38:1979 (1965), and Chem. Ber., 788 and 2024 (1970).
Each of the above techniques which provide the R1 and R2 groups are carried out in solvents as discussed above. These techniques which do not produce an acid product in the course of the reaction, of course, do not necessitate the use of an acid scavenger in the reaction mixture.
When a formula I compound is desired in which R1 and R2 is xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), the formula I dihydroxy compound is reacted with, for example, a derivative of the appropriate sulfonic acid such as a sulfonyl chloride, bromide, or sulfonyl ammonium salt, as taught by King and Monoir, J. Am. Chem. Soc., 7:2566-2567 (1975). The dihydroxy compound also can be reacted with the appropriate sulfonic anhydride. Such reactions are carried out under conditions such as were explained above in the discussion of reaction with acid halides and the like.
Further formula I compounds may then be formed as desired. Specific preparations of compounds of the present invention are described below. Modifications to the above methods may be necessary to accommodate reactive functionalities of particular substituents. Such modifications would be both apparent to, and readily ascertained by, those skilled in the art.
Although the free-base form of formula I compounds can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. Thus, the compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, xcex2-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.
The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.